The Time When Serendipity Delivered Proteins Orally

The oral delivery of proteins like vaccines and insulin is one of the holy grails of modern medicine. In this post, I describe how our current approach came to be and why we made the controversial decision to deliver insulin.

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In 2015, my talented Ph.D. student, Nick Lamson, was trying to identify intestinal permeation enhancers from raw fruits and vegetables. Under the suspicious eye of EH&S, he’d whip up fruit smoothies with our Amazon-purchased kitchen blender and apply them to sheets of intestinal cells.  

Nick noticed that some fruits increased intestinal cell permeability and that these increases varied when he filtered the fruit smoothies. Since smoothies are really just aqueous colloidal suspensions, we wondered if there was something about the colloids that was affecting the intestinal cells.  

This, it turns out, was a critical moment.
Should we indulge our curiosity with a set of side experiments?
Do we stick our curiosity in a drawer because there is no money for this work, anyway?

There was no divine intervention that told us “choose option A, you will get a Nature BME paper”. Ignorant to the possibility of serendipity, we simply gave our curiosity a bit of free rein. We decided to find some colloids with well-defined sizes. Nick settled on silica nanoparticles, because they weren’t too expensive and came in a range of diameters, from 20 to 1200 nm. We didn’t expect much from these experiments and were surprised to find that treatment of intestinal cells with the smallest silica nanoparticles resulted in 25 times more drug transport than without treatment. (!!)  

With these striking data, we realized that we might have found something special. So, for the next 3+ years, we cobbled together the time and funding to translate our cell culture results into animal studies. In mice, we demonstrated that silica nanoparticle permeation enhancers enable the oral delivery of two proteins: insulin and exenatide (both used to treat diabetes). 


Now, there are plenty of scientists who aren’t wild about the use of insulin in oral delivery studies. Their distaste stems from the numerous reports of oral insulin delivery over the past several decades that have yielded exactly zero products. There is also widespread skepticism that an oral insulin formulation will ever become a reality. One of the biggest translational challenges is that insulin must be dosed in response to ingested food; but that same food can clog up the gastrointestinal tract and prevent effective delivery.  

Despite the concerns, we looked at insulin for two reasons. First, it’s an especially easy drug to use in the lab. It’s relatively small and inexpensive, and its delivery causes an effect that’s simple to measure. From a single drop of blood, we assess decreasing blood sugar (i.e. glucose) using test strips and glucometers purchased from a drug store. The second reason is more philosophical. An oral form of insulin would more positively impact patients than any other protein medication. That’s because diabetes is one of the most prevalent chronic diseases in the world, and many patients must inject themselves 3-4 times a day to keep their diabetes under control. Which, honestly, sounds terrible. Three to four injections every day, for the rest of your life.  

My students and I don’t presume that our silica nanoparticles will solve the oral insulin problem. But we feel good showing that it is possible with a new kind of permeation enhancer under controlled circumstances. As academic researchers, we’re in a position to take the first steps, and so that’s what we do.


Finally, please don’t assume our work is high quality just because it’s been published in a journal that includes the word Nature. Read the paper for yourself and make your own judgements about the rigor of the experiments and the likelihood of impact. I hope you like the paper as much as we do. 


You can read the paper at:
Lamson, N.G., Berger, A., Fein, K.C., and Whitehead, K.A. Anionic nanoparticles enable the oral delivery of proteins by enhancing intestinal permeability. Nature Biomedical Engineering, doi: 10.1038/s41551-019-0465-5, 2019.  

Image in header attributed to nanoComposix, our silica nanoparticle vendor.  

Correspondence: Prof. Kathryn Whitehead,
Read more about the Whitehead Lab at

Kathryn Whitehead

Associate Professor, Carnegie Mellon University

Kathryn A. Whitehead is an Associate Professor and Dean’s Career Fellow in the Departments of Chemical Engineering and Biomedical Engineering (courtesy) at Carnegie Mellon University. Her lab develops RNA and protein drug delivery systems and has a long-term goal of predicting the behavior of delivery materials in humans. She received an H.B.Ch.E Degree with Distinction from the University of Delaware (2002) and a Ph.D. in chemical engineering from the University of California, Santa Barbara (2007) before serving as an NIH Ruth L. Kirschstein Postdoctoral Fellow at the Massachusetts Institute of Technology (2008 – 2012). Prof. Whitehead is the recipient of numerous awards, including the NIH Director’s New Innovator Award, the DARPA Young Faculty Award, the DARPA Director’s Fellowship, the ASEE Curtis W. McGraw Research Award, and the Kun Li Award for Excellence in Education. Prof. Whitehead was named as a Pioneer on the MIT Technology Review’s Innovators Under 35 list in 2014 as well as one of the Brilliant Ten by Popular Science in 2015. Her publications have been cited over 5,000 times, and several of her patents have been licensed and sublicensed for reagent and therapeutic use.